title: Cyclin-dependent kinase 5 promotes pancreatic β-cell survival via Fak-Akt signaling pathways.
abstract: OBJECTIVE
  Cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated protein 1-like 1 has recently been linked to type 2 diabetes by genome-wide association studies. While CDK5 and its regulatory protein p35 are both expressed and display enzymatic activity in pancreatic β-cells, their precise role in the β-cell remains unknown. Because type 2 diabetes is characterized by a deficit in β-cell mass and increased β-cell apoptosis, we investigated the role of CDK5 in β-cell survival.
  
  
  METHODS
  We used INS 832/13 cells, rat islets isolated from wild-type or human islet amyloid polypeptide (h-IAPP) transgenic rats, and pancreatic tissue from rats and humans with and without type 2 diabetes and investigated the effect of CDK5/p35 inhibition (by small interfering RNA or by chemical inhibition) as well as CDK5/p35 overexpression on β-cell vulnerability to apoptosis.
  
  
  RESULTS
  CDK5 inhibition led to increased β-cell apoptosis. To identify the mechanisms involved, we examined the phosphorylation state of focal adhesion kinase (Fak)(Ser732), a known target of CDK5. Following CDK5 inhibition, the phosphorylation of Fak(Ser732) decreased with resulting attenuation of phosphatidylinositol 3-kinase (PI3K)/Akt survival pathway. Conversely, CDK5 overexpression increased Fak(Ser732) phosphorylation and protected β-cells against apoptosis induced by the inhibition of the β-1 integrin signaling pathway. Also, Fak(Ser732) phosphorylation was less abundant in β-cells in both h-IAPP transgenic rats and humans with type 2 diabetes.
  
  
  CONCLUSIONS
  This study shows that by regulating Fak phosphorylation and subsequently PI3K/Akt survival pathway, CDK5 plays a previously unrecognized role in promoting β-cell survival.
authors.affiliation: Larry Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. mdaval@mednet.ucla.edu
authors.forename: Marie
authors.initials: M
authors.lastname: Daval
authors.forename: Tatyana
authors.initials: T
authors.lastname: Gurlo
authors.forename: Safia
authors.initials: S
authors.lastname: Costes
authors.forename: Chang-Jiang
authors.initials: CJ
authors.lastname: Huang
authors.forename: Peter C
authors.initials: PC
authors.lastname: Butler
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D058228:Islet Amyloid Polypeptide / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D051381:Rats; D055647:Rats, Transgenic; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D058228:Islet Amyloid Polypeptide; D034741:RNA, Small Interfering; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051360:Cyclin-Dependent Kinase 5; D051057:Proto-Oncogene Proteins c-akt